Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5'-Nucleotidase has been purified from rat glioblastoma cells (Rugli cells). The enzyme has been solubilized from plasma membranes by using Triton X-100 and CHAPS. Two affinity chromatographies on concanavalin A and 5'-AMP-Sepharose render the purified enzyme with a high specific activity (76.36 mumol AMP.min-1.mg-1). The purified enzyme gives a single polypeptide band on SDS-PAGE with an apparent molecular mass of 74 kDa. Active forms with an apparent molecular mass of 135 kDa and 268 kDa are observed when the purified enzyme is analyzed by gel filtration in the presence of either 0.6% sodium deoxycholate or 0.1% Triton X-100, respectively. The purified 5'-nucleotidase presents optimum activity at pH 7.8-8.1 either in the presence or in the absence of Mg2+. A linear Arrhenius plot is observed in the 25-46 degrees C temperature range and an activation energy of 33.7 KJ/mol is calculated. The enzyme is inhibited by EDTA; the activity is partially restored by different divalent cations as Zn2+, Mn2+, and Co2+. The hydrolysis of nucleosides 5'-monophosphate shows Michaelis kinetic. The enzyme is inhibited by nucleosides di- and triphosphate. 5'-Nucleotidase is a glycoprotein, being its activity inhibited at different extent by various lectins.
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PMID:Isolation and characterization of the ecto-5'-nucleotidase from a rat glioblastoma cell line. 148 Jan 62

Many studies have established that a select subset of normal cellular genes are altered in cancer by point mutations, translocations or gene amplification. However, the vast majority of genetic changes that occur in neoplastic cells have not yet been identified. In an attempt to identify some of these other genetic changes, we have recently isolated a gene, GLI, by virtue of its amplification in a human glioblastoma. Subsequently, GLI was found to be amplified in other human glioblastomas (ref. 3 and unpublished data). To understand better the role of GLI in human neoplasia, we have now cloned the GLI complementary DNA (cDNA) and determined its nucleotide sequence. Analysis of the predicted translation product reveals that it contains five repeats of a DNA binding consensus sequence (zinc finger) originally described in Xenopus Transcription Factor III A (TFIIIA). Furthermore, these zinc fingers contain sequence elements that suggest the GLI gene product is a member of the recently described Kruppel family of zinc finger proteins. Additional experiments demonstrate that GLI is an evolutionarily conserved gene that is expressed in embryonal carcinoma cells but not in most adult tissues. The link between the developmentally important Kruppel family of genes and GLI is interesting considering the similarities between developing embryonic and neoplastic tissue.
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PMID:The GLI gene is a member of the Kruppel family of zinc finger proteins. 283 61

Human HT1080 fibrosarcoma cells, subclone H4, express little or no Egr-1 (Zif/268, Krox 24), an early growth response gene encoding a transcription factor. Phorbol ester (but not serum) treatment only can elicit a small increase in Egr-1 expression in H4, in contrast to the normally rapid, high transient expression of Egr-1 observed after the addition of a wide range of stimulating agents to normal or immortalized cell lines. Because several human tumor cell lines express little Egr-1, we tested the hypothesis that this loss was causal to transformation. We report here that the expression of exogenous mouse Egr-1 in H4 cells inhibits transformed growth in a dose-dependent manner and significantly suppresses tumorigenicity in athymic mice. By overexpression of the fragment in Egr-1 that is responsible for its DNA-binding activity, the zinc-finger domain, we show that this domain has a similar activity. Moreover, the expression of antisense mRNA encoding the DNA-binding domain increases the transformed character of the H4 cells. One possible conclusion is that endogenous Egr-1-like genes perform growth-regulatory functions. Other human tumor lines are also growth suppressed by Egr-1 overexpression including ZR-75-1 breast carcinoma, U251 glioblastoma, and to a lesser extent, SAOS-2 osteosarcoma cells. These results are surprising in light of the "early growth response" character of Egr-1 but extend our earlier report of suppression of growth in v-sis-transformed NIH3T3 cells.
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PMID:Egr-1 negatively regulates human tumor cell growth via the DNA-binding domain. 758 51

Antioxidants and reactive oxygen species are considered to play an important role in experimental in vivo carcinogenesis studies. We attempted in this study to evaluate the repercussions on the antioxidant and lipid peroxide status of the growth of human malignant tumors xenografted into athymic mice. We selected three tumor models: two urothelial carcinomas (bladder tumors stage 3) and one brain tumor (glioblastoma stage 4). All these tumors exhibited a fast growth pattern when xenografted into athymic mice. Tumoral tissue was implanted subcutaneously. After growth establishment each tumor size was measured at regular intervals: every 2 d for bladder tumor and twice a week for glioblastoma. The period of observation was 3 wk for bladder tumors and 5 wk for glioblastoma. At the end of the observation period, all mice were sacrificed; tumoral tissue was taken and blood collected. Superoxide dismutase activity (SOD), glutathione peroxidase activity (GSH-Px), zinc (Zn), selenium (Se), and thiobarbituric acid reactive substances (TBARS) were measured in blood. TBARS alone were measured into tumoral tissue. A modification of the antioxidant blood status was observed in mice xenografted with bladder tumors with decrease in Se status and GSH-Px activities, and increase in TBARS. Such an effect was absent in mice xenografted with glioblastoma. It would appear that an oxygen-mediated stress exists in the animal bearing an implanted tumor compared with the control group, and that tumoral tissue itself is able to induce an oxidative stress into its host. All this leads to a disturbance of the antioxidant defense system.
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PMID:Antioxidant status and lipid peroxidation in athymic mice xenografted with two types of human tumors. 777 35

In vitro, when using low concentrations of ferritin (ng/ml) or CaCl2 (micrograms/ml), multiplication of a human, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioblastoma cell line (U251) is enhanced 1.5 to 2 times more actively than multiplication of a normal astrocyte line (CRL 1656). Ferritin and Ca2+ ions exhibit a marked effect on DNA isolated from these cells: glioblastoma DNA relaxation is strongly increased (as evidenced by increased 260 nm ultraviolet absorbance), being from 5 to 6 times that of astrocyte DNA, which remains only slightly affected. Under identical experimental conditions, Zn2+ and gallium ions selectively inhibit glioblastoma cell multiplication but at the same concentrations do not inhibit astrocyte multiplication. Ultraviolet absorbance measurements demonstrate that both of these agents condense relaxed glioblastoma DNA in vitro. Zn2+ or gallium ions added to culture medium containing stimulatory concentrations of ferritin or Ca2+ ions selectively and strongly inhibit enhancement of glioblastoma cell multiplication by these mitogens while not affecting normal multiplication of astrocytes.
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PMID:Differential effects of ferritin, calcium, zinc, and gallic acid on in vitro proliferation of human glioblastoma cells and normal astrocytes. 814 3

Calmodulin (CaM) is involved in cellular processes that are vital to cell proliferation and viability. Elevated CaM content is seen in transformed cells. Anti-CaM compounds alone are cytotoxic to tumor cells and are synergistic with certain cancer chemotherapeutic agents. However, all known CaM antagonists are nonselective, complicating interpretation of these studies. To more rigorously analyze the relationship between CaM protein expression and the behavior of cancer cells, tumor-derived cell lines were engineered such that CaM concentration could be manipulated by overexpressing CaM RNA. A full-length rat CaM I cDNA was inserted into the mammalian expression vector pMTCB6+ so that either CaM mRNA (sense) or antisense RNA was expressed under the control of an inducible metallothionein promoter. Constructs were introduced into C6 glioblastoma cells by liposome-mediated transfection and colonies were selected in G418. Significantly fewer clones were recovered from transfections with antisense vectors compared to CaM sense RNA or control (empty) vector alone. This difference was attributed to the cytotoxic effects of antisense CaM RNA as opposed to differences in transfection efficiencies. CaM expression was analyzed at the RNA level by Northern blotting and CaM protein concentrations were quantitated by immunofluorescence. Clones were identified in which CaM protein could be increased or decreased following exposure to zinc ions. Changes in CaM mRNA preceded changes in CaM protein by several hours. Overexpression of CaM had no significant effects on the growth of C6 cells. However, reductions in CaM lead to decreased growth rates of C6 cells and lowered cell viability.
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PMID:The effects of altered cellular calmodulin expression on the growth and viability of C6 glioblastoma cells. 911 56

Various metal ions were investigated for their ability to modify the radical intensity and cytotoxic activity of sodium ascorbate or ascorbic acid. The addition of metal ions, such as Cu+, Cu2+, Fe2+, Zn2+, Mn2+ and Fe3+, dose-dependently enhanced the ascorbyl radical intensity whereas Na+, K+, Ca2+ and Mg2+ were totally inactive. The enhancement of ascorbyl radical intensity by metal ions was tightly coupled with the accelerated degradation of ascorbate. Addition of either serum or albumin significantly reduced the stimulation effect of Cu2+, and almost completely eliminated that of Fe3+ and Zn2+. The noncytotoxic concentration of Cu2+ significantly enhanced the cytotoxicity of ascorbate against cultured human glioblastoma T98G cell line. The present data suggest the possible role of metal ions in the regulation of the biological activity of ascorbate.
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PMID:Effect of metal ions on radical intensity and cytotoxic activity of ascorbate. 913 59

Insulin-like growth factor binding proteins (IGFBPs) are found both associated with cells and in extracellular fluids. Cell-associated IGFBPs increase [125I]-IGF binding to cell monolayers, whereas extracellular (soluble, released) IGFBPs decrease binding. In the current study, we show that either IGFBP-3 or IGFBP-5 are the major forms of IGFBP released from monolayers of human GM10 fibroblasts, T98G glioblastoma cells and forskolin-treated bovine MDBK cells. IGFBPs represent the most abundant [125I]-IGF-I binding site on GM10 and T98G cell monolayers, but 4-17% of the total cell-associated IGFBPs are released from the cell monolayer at 8 degrees C during their quantification. Most of the IGFBPs (> 70%) are released from MDBK cells. Quantitative estimates of [125I]-IGF binding to the cell monolayers are altered because of the ability of the released IGFBPs to reduce the amount of radiolabeled ligand that is available to bind to the cell surface. Lanthanum (La3+) depresses IGFBP release from all three cell types (> 80% for GM10 and T98G cells and > 65% for MDBK cells). The effect was cation specific, noted with La3+ or Zn2+ but not with either Mn2+, Sr2+ or Se3+. The effect was also IGFBP specific; La3+ markedly depressed the release of IGFBP-3 and IGFBP-5, but had less of an effect on IGFBP-2 and IGFBP-4. Concomitant with a decrease in IGFBP-3 and IGFBP-5 release, La3+ caused an increase in [125I]-IGF-I binding to cell-associated IGFBPs and type I IGF receptors. The released soluble IGFBPs have a three- to 20-fold greater affinity (Ka) for [125I]-IGF-I compared to cell-associated IGFBPs. La3+ did not alter the affinity constants of cell-associated IGFBPs. In summary, we have identified a means to prevent loss of IGFBPs from cell monolayers during binding assays. This procedure will be useful in accurately quantifying the levels of IGFBPs on cell monolayers and in determining the role of cell-associated IGFBPs in controlling IGF activity. Retention of cell-associated low affinity IGFBPs may be important in controlling the size of the pericellular IGF pool and in regulating IGF-I access to the type IIGF receptor.
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PMID:Use of lanthanum to accurately quantify insulin-like growth factor binding to proteins on cell surfaces. 921 26

The current studies quantified the effect of the multivalent cations zinc, cadmium, lanthanum, chromium, and gold (Zn2+, Cd2+, La3+, Cr3+, and Au3+) on [125I]-insulin-like growth factor ([125I]-IGF) binding to T98G human glioblastoma cells. The major binding site for the IGFs on T98G cells is IGF binding protein-5 (IGFBP-5), as determined by affinity labeling. Competitive binding studies, using either [125I]-IGF-I or [125I]-IGF-II, indicated that La3+ and Cr3+ did not affect [125I]-IGF-I or [125I]-IGF-II binding to cell-associated IGFBP-5. Zn2+, Au3+, and Cd2+ depressed binding of both [125I]-IGF-I and [125I]-IGF-II. [125I]-IGF-I and [125I]-IGF-II binding resulted in nonlinear concave-down Scatchard plots, indicating the presence of high- and low-affinity equilibrium constant of association (Ka) sites. Assuming a preexisting asymmetric model with independent high (KaHi) and low (KaLo) sites; Zn2+, Cd2+, and Au3+ eliminated KaHi and Zn2+, and Au3+ lowered KaLo, compared with control values. The same results were found, independent of whether [125I]-IGF-I or [125I]-IGF-II was used. Similarly, assuming a ligand-induced model of negative cooperativity, all three cations eliminated the initial affinity for the high affinity sites (Ka), whereas Zn2+ and Au2+ reduced the final affinity for the low affinity sites (Kf). Dose-response studies indicated that Zn2+, Au3+, and Cd2+ depressed binding with half-maximal activities of approximately 20 microM, 14-60 microM, and 50-65 microM, respectively. Zn2+, Au3+, and Cd2+ bind to similar sites on proteins (a zinc-binding motif), indicating similar mechanisms of action. A zinc-binding motif is present within the IGFBPs but not the IGFs. We demonstrate, for the first time, that multivalent cations have the potential to modulate IGF activity by decreasing the amount of IGF bound to cell-associated IGFBP-5.
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PMID:Multivalent cations depress ligand binding to cell-associated insulin-like growth factor binding protein-5 on human glioblastoma cells. 952 81

The relationship between the degree of the expression of Cu/Zn SOD, GST-pi and bcl-2 in the initial and recurrent tumor tissue after radiotherapy and/or chemotherapy and the cellular heterogeneity obtained from DNA content by image cytometry was investigated. Subjects were 7 patients who had glial tumors which were surgically removed at onset and removed a second time at recurrence. Radiotherapy and chemotherapy were also administered after initial resection. Immunoreactivity for copper/zinc super oxide dismutase (Cu/Zn SOD), GST (glutathione-S-transferase)-pi, and bcl-2 were evaluated from routinely prepared tissue blocks. Tumors were classified into two groups by cytometric analysis of DNA ploidy in the G2M cell cycle phase. One tumor group consisted of single clonal cells in both the initial and recurrent tumors and the other group consisted of tumors with polyclonal cells in the initial and recurrent tumor. In this study, one patient (case 3) with single clonal cell glioblastoma at recurrence did not show high Cu/Zn SOD activity after radiotherapy and chemotherapy but showed a short survival time after recurrence. In three patients (cases 1, 2, 3) with single clonal-cell glioblastoma, the recurrent tumor cells showed high GST-pi immunoreactivity and survival time was short after recurrence. Tumor cells in two patients (cases 5, 7) with single clonal cell anaplastic glioma at recurrence, showed high GST-pi immunoreactivity and had a short survival time after recurrence. In three single clonal glioblastomas (cases 1, 2, 3), the recurrent tumor showed the increased bcl-2 immunoreactivity and showed a short survival time after recurrence. In two patients (case 5, 7) with single clonal cell anaplastic glioma at recurrence, tumor cells showed a high bcl-2 immunoreactivity and these patients showed a short survival time after recurrence. Although the number of subjects is very small, our study shows that the immunoreactivity of bcl-2 and GST-pi in malignant gliomas may be very important factors in radio- and chemosensitivity, and shows that GST-pi is induced by radiation and anti-cancer drugs.
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PMID:Expression of enzymes and oncogene induced after radiotherapy and/or chemotherapy in patients with brain tumors. 1143 58


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